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1 Antimicrobial Resistance and Usage Patterns in Europe: Focus on Dutch-Belgian Differences and Complementarity & Lessons for the Future Dominique L. Monnet Antimicrobial Resistance Surveillance Unit, Dept. of Antimicrobial Resistance & Hospital Hygiene, Statens Serum Institut, Copenhagen, Denmark

2 MRSA in Europe, < 1% 1-2% 5.5% 2-29% 3-35% Source: Voss A, et al. Eur J Clin Microbiol Infect Dis 1994;13:5-55.

3 Methicillin-Resistant Staphylococcus aureus (MRSA) from Blood, 21 < 3% 3-9% 1-29% > 3% Source: EARSS. Available from: URL:

4 Ticarcillin-Resistant Pseudomonas aeruginosa in Europe (ICU NIs only), 1992 no data % 15-25% 5-65% 8% Source: EPIC Study (Régnier B. Pathol Biol 1996;44:113-23).

5 The World According to Human Bacterial Pathogens and Their Habitat Food Animals Humans Humans le MONDe de la Résistance Intrinsèque et Acquise aux ANtibiotiques ;-). H Pseudomonas aeruginosa Acinetobacter baumannii MRSA Salm. Camp. E. coli S. pneumoniae H. influenzae S. aureus E. coli S. aureus

6 Penicillin-Non Susceptible Streptococcus pneumoniae (PNSP) from Sterile Sites < 3% 3-9% 1-29% > 3% Source: EARSS. Available from: URL: (Accessed: 31/7/22)

7 Erythromycin-Resistant Streptococcus pneumoniae from Sterile Body Sites < 3% 3-9% 1-29% > 3% Source: EARSS. Available from: URL: (Accessed: 31/7/22)

8 Erythromycin-Resistant Streptococcus pneumoniae from Community-Acquired Respiratrory Tract Infections, 1998 no data -5% 5.1-1% 1.1-3% >3% Sources: Alexander Project, FINRES, STRAMA and DANMAP.

9 Lower use of macrolides (less exposed, shorter duration) Lower use of other antimicrobials Better compliance (dose, intervals) More rational utilization of antimicrobials? Lower Percentage of Erythromycin-R S. pneumoniae in Community-Acquired RTIs Different population? Age (extremes) Respiratory and other diseases Pre-school facilities Long-term care? Better living conditions Socio-economic status Climate? Less travel Different clones Less cross- transmission? Better protection against disease? Vaccination Breast feeding

10 Source: Cars O, et al. Lancet 21; 357:

11 Is It Relevant to Examine Overall Antibiotic Consumption? (1)! Overall antibiotic consumption (no. DDD) is related to no. antibiotic prescriptions and no. persons exposed to antibiotics! It only accounts for some aspects of antibiotic misuse, e.g. prescribed when not indicated, duration too long, but cannot account for errors in dosing or low compliance! Nevertheless, if the antibiotic course prescribed is not completed, then it is probably used at another occasion

12 Is It Relevant to Examine Overall Antibiotic Consumption? (2)! Antibiotics have an effect not only on the patients who are treated but also an effect on other patients and the environment! Relationship between antibiotic use and resistance is an ecological problem!! There is room for improvement considering the extent of variations both in the amount and the pattern of use among European countries

13 Erythromycin-Resistant Streptococcus pneumoniae and Macrolide Consumption in EU Member States, E rythrom ycin-resistant S. pneum oniae in 1998 (% ) Consum ption of m acrolides and lincosam ides in prim ary health care in 1997 (D D D /1, inh.-days) Sources: Alexander Project, FINRES, STRAMA, DANMAP, and Cars O, et al. Lancet 21; 357:

14 Source for resistance data: Alexander Project. Source for antimicrobial consumption data: Cars O, et al. Lancet 21; 357: STATENS SERUM INSTITUT %Erythromycin-R S. pneumoniae (Logodds transf.) and Antimicrobial Consumption in Europe Independent variable (ATC group) No. EU countries R 2 P Tetracyclines (J1A) <.1 NS Extended spectrum penicillins (J1CA, Ln tr.).74 <.1 Beta-lactamase sensitive penicil. (J1CE, Ln tr.).49 (-).5 Beta-lactamase resistant penicillins(j1cf) <.1 (-) NS Cephalosporins (J1DA).55.3 Trimethoprim (J1EA, Ln tr.) <.1 NS Macrolides and lincosamides (J1F).82 <.1 Fluoroquinolones (J1MA, Ln tr.).32.4 Other antibacterials (from ATC group J1). NS

15 12 Patients Interviews and Misuse of Antibiotics, Saved part of course for future use (%) 4 2 Claimed to finish course (%) UK France Belgium Turkey Italy Morocco Columbia Spain Thailand Source: Pechère J-C. Clin Infect Dis 21; 33 (Suppl 3): S17-S173.

16 %Erythromycin-R S. pneumoniae (Logodds transf.) and Factors That Might Facilitate Cross-Transmission Independent variable Preschool children taking up offers of preschool services (%) Population whose daily caring activities prevent them from undertaking the same amount of paid work (%) Persons living in households with children (%) Persons in overcrowded households (%, Ln transf.) Households lacking at least one of three basic amenities, i.e. bath, toilet or hot water (%, Ln transf.) Persons living below the poverty line (%, Ln tr.) Nights spent in EU countries with high %Ery-R S.p. (per 1, inh.-days, incl. domestic, Ln transf.) No. EU countries Sources: Danish National Institute of Social Research, EC Eurostat, and European Travel Commission (ETC) Tourism Statistics R (-) < P.6 NS.3.5 NS.6.6

17 %Erythromycin-R S. pneumoniae (Logodds transf.) and Susceptibility to/protection against Disease Independent variable Population whose age is <= 4 years (%) Population whose age is >65 years (%) Daily cigarette smokers (%) Households that cannot afford to keep home adequately warm (%, Ln transf.) Distributed doses of pneumococcal vaccine (per 1, inhabitants, 1996, Ln transf.) Infants breastfed at 3 months of age (%, Ln tr.) Persons with at least 3 hours of physical activity (leisure) in a typical week (%) No. EU countries <.1 (-) <.1.47 (-).29 (-) Sources: U.S. Bureau of the Census, EC Eurostat, WHO Regional Office for Europe, and Fedson DS. Clin Infect Dis 1998;26: R 2 P NS NS NS NS NS.1.5

18 Multiple Linear Regression Models for Prediction of %Erythromycin-R S. pneumoniae (Logodds transf.): Preliminary Results Independent variable β t P (Constant) <.1 Macrolides and lincosamides (J1F) <.1 R 2 =.817 Independent variable β t P Macrolides and lincosamides (J1F) Infants breastfed at 3 months of age (%, Ln tr.) R 2 =.959

19 Factor Analysis (PCA) of %ERSP (Logodds transf.) and Other Variables: Preliminary Results (1) Variable %Erythromycin-R S. pneumoniae (Logodds tr.) Macrolides and lincosamides (J1F) Cephalosporins (J1DA) Extended spectrum penicillins (J1CA, Ln transf.) Beta-lactamase sensitive penicil. (J1CE, Ln trsf.) Fluoroquinolones (J1MA, Ln transf.) Persons with at least 3 hours of physical activity (leisure) in a typical week (%) Infants breastfed at 3 months of age (%, Ln transf.) Persons in overcrowded households (%, Ln transf.) Persons living in households with children (%) Component

20 Factor Analysis (PCA) of %ERSP (Logodds transf.) and Other Variables: Preliminary Results (2) ln(sup1_room) rysp))

21 Source: EARSS, May 2. Available from: URL: STATENS SERUM INSTITUT Penicillin-Non Susceptible Streptococcus pneumoniae (PNSP) from Sterile Sites, 2 %PNSP no data < >3

22 Source: Bronzwaer SLAM, et al. Emerg Infect Dis 22; 8: STATENS SERUM INSTITUT Penicillin-Non Susceptible S. pneumoniae from Sterile Sites ( , log odds transf.) & Consumption of Beta-Lactams (1997) in the EU

23 %PNSP (Logodds transf.) and Antimicrobial Consumption in Europe Independent variable (ATC group) No. EU countries R 2 P Tetracyclines (J1A) <.1 NS Extended spectrum penicillins (J1CA, Ln tr.).66 <.1 Beta-lactamase sensitive penicil. (J1CE, Ln tr.).31 (-).4 Beta-lactamase resistant penicillins(j1cf) <.1 (-) NS Cephalosporins (J1DA).74 <.1 Trimethoprim (J1EA, Ln tr.) <.1 NS Macrolides and lincosamides (J1F).71 <.1 Fluoroquinolones (J1MA, Ln tr.).26.6 Other antibacterials (from ATC group J1).18 NS Source for resistance data: EARSS. Source for antimicrobial consumption data: Cars O, et al. Lancet 21; 357:

24 Multiple Linear Regression Model for Prediction of %PNSP (Logodds transf.): Preliminary Results Independent variable β t P (Constant) <.1 Cephalosporins (J1DA) <.1 R 2 =.74

25 Nalidixic Acid-Resistant Escherichia coli from Community-Acquired Uncomplicated UTIs in Women, ECO-SENS Project, no data <3% 3.1-6% 6.1-1% >1% Source: Kahlmeter G. Clin Microbiol Infect 21;7(Suppl 1): 86.

26 %Nalidixic Acid-Resistant E. coli (Logodds transf.) and Antimicrobial Consumption in Europe Independent variable (ATC group) No. EU countries R 2 P Tetracyclines (J1A).11 NS Extended spectrum penicillins (J1CA, Ln tr.).31.4 Beta-lactamase sensitive penicil. (J1CE, Ln tr.).64 (-).1 Beta-lactamase resistant penicillins(j1cf) <.1 (-) NS Cephalosporins (J1DA).2 NS Trimethoprim (J1EA, Ln tr.) <.1 (-) NS Macrolides and lincosamides (J1F).35.3 Fluoroquinolones (J1MA, Ln tr.).49.5 Other antibacterials (from ATC group J1).15 NS Source for resistance data: Kahlmeter G, et al. ECO.SENS. Source for antimicrobial consumption data: Cars O, et al. Lancet 21; 357:

27 Pathways of Antimicrobial Use in Primary Health Care Infection / Microorganism Prescription of antimicrobials Patient Over-the-counter dispensation of antimicrobials GP or specialist Pharmacist

28 Pathways of Antimicrobial Use in Primary Health Care (1) Infection / Microorganism Prescription of antimicrobials Patient Over-the-counter dispensation of antimicrobials GP or specialist Pharmacist

29 Different Susceptibility to/protection Against Infectious Diseases or Incidence of Community-Acquired Infectious Diseases?! Demography! Incidence of certain diseases, e.g. diabetes, cancer! Living conditions: overcrowding, day care, hygiene! Protecting factors: breastfeeding, vaccinations! Incidence of community-acquired infections: bacterial RTIs, influenza-like illness! Prevalence of resistance among communityacquired bacteria

30 Source: U.S. Bureau of the Census, WHO HFA database & EC Eurostat. STATENS SERUM INSTITUT Characteristics of the Population of 3 EU Member States, (1) Belgium Netherlands Denmark Population (million inhab.) Pop. -4 year old (%) Pop. > 65 year old (%) Urban population (%, WHO) Pop. density (inhab./km 2 ) Pop. in overcrowded homes (%) Pop.below poverty line (%) Pop. cannot afford to keep home adequately warm(%) Pop. without at least one of bath, toilet or hot water (%) 7 1 3

Influenza-Like Illness Activity and Overall Consumption of Systemic Antibacterials (ATC J1) in Primary Health Care, EU Member States, 1997 Influenza-Like Illness Activity, 1997 Source: FluNet.

31 Influenza-Like Illness Activity and Overall Consumption of Systemic Antibacterials (ATC J1) in Primary Health Care, EU Member States, 1997 Influenza-Like Illness Activity, 1997 Source: FluNet. Available from: Consumption of antibacterials for systemic use ATC J1 (DDD per 1, inh-days) 5 4 DDD/1, inh.-days No repororadic/loregional No activity Sporadic Regional / / No report / Local Widespread

32 Overall Consumption of Systemic Antibacterials (ATC J1) in Primary Health Care and Breastfeeding, EU Member States, Consum ption of antibacterials for system ic use A TC J1 (DDD per 1, inh-days, 1997) R 2 =.28 P=.5 See also: Breastfeeding & Respiratory Illness During Childhood Wilson AC, et al. BMJ 1998;316: Infants breastfed at 3 m onths (%, , UK : at 4 m ths) Source: Health For All database, WHO.

33 Source: WHO Health For All database & EC Eurostat. STATENS SERUM INSTITUT Characteristics of the Population of 3 EU Member States, (2) Belgium Netherlands Denmark Daily smokers (%) Persons living in households with children (%) Preschool children taking up offers of preschool services (%) Respiratory diseases (no./1,) 1, ,448 Distrib. doses pneumococcal vaccine (no./1, inhab., 1996) Pop. with at least 3 hours of physical activity (leisure) in typical week (%) Infants breastfed at 3 months (%)

34 Labelling of Disease and Attitude Towards Upper Respiratory Tract Infections Flanders Netherlands "A cold" "Bronchitis" "Flu" Unlabelled (e.g., coughing, runny nose) Other (e.g., "sinusitis", "angina") Consulting a doctor Self-medication Nursing one's illness Source: Deschepper R, et al. Pat. Educ. Counsel. 22;48:

35 Prescription of Antimicrobials and Bacteriological Testing for Acute Tonsillitis, Prescribed antibiotics (%) - penicillin V (%) - amoxicillin (%) - macrolide (%) Bacteriological tests (%) No test, prescribed antibiotics (%) Belgium (n=44 pts) Netherlands (n=62 pts) Source: Touw-Otten FWMM & Staehr Johansen K. Family Pract. 1992;9:

36 Pathways of Antimicrobial Use in Primary Health Care (2) Infection / Microorganism Prescription of antimicrobials Patient Over-the-counter dispensation of antimicrobials GP or specialist Pharmacist

37 Factors that Influence Prescription (1): Related to the Patient! Cultural differences: perceived severity of illness! Social issues: pressure to be back at work/day care! Economical issues: income vs. price! Education and information: information campaigns! Health care system and regulation: cost of GP consultation, price of antimicrobials after reimbursement, direct access to specialists(?)! Promotion: direct-to-consumer advertising

38 Factors that Influence Prescription (2): Related to the GP or the Specialist! Cultural differences: willingness to help! Education and information: information campaigns, guidelines, drug compendia, registered indications for a specific antibiotic, promotional material provided by representatives! Health care system and regulation: type of healthcare system, rostering of patients, GP remuneration, working hours, point-of-care diagnostic tests, economical incentives, fear of litigation! Pharmaceutical industry and promotion: competition among pharmaceutical companies, intensity of promotional activity to GPs/specialists

39 Source: Deschepper R, et al. Pat. Educ. Counsel. 22;48: STATENS SERUM INSTITUT Attitude Towards Upper Respiratory Tract Infections, by Region and Religion Catholic, Catholic, Protestant, Nonchurchg., FL (n=6) NL (n=3) NL (n=8) FL (n=9) Nonchurchg., NL (n=4) Healing power of body (%) Fear of complications (%) Belief in antibiotics - sceptic (%) strong believer (%) 5 44 Use of antibiotics during the past 5 years - none/low (%) high/very high (%) 5 44

40 What About Cultural Differences in the European Union? 5 5 Consumption of antibacterials for systemic use ATC J1 (DDD per 1, inh-days) DDD/1, inh.-days P=.1 Majority protestant Majority catholics Majority Majority protestants catholics WELL, INSTEAD OF ALWAYS POINTING AT CULTURAL DIFFERENCES TO EXCUSE OUR LACK OF ACTION OR PREVIOUS MISTAKES, MAY BE WE COULD LEARN FROM (OTHER) DIFFERENCES AMONG COUNTRIES OR REGIONS AND IDENTIFY AREAS FOR IMPROVEMENT!

41 Antimicrobial Prescribing Attitudes of GPs Can Be Modified Through Peer-Review/Education!! Netherlands: peer-review groups (incl. collaborating pharmacist), mandatory clinical audits every 2 or 4 weeks (pharmacist reviews prescriptions)! Belgium: no such peer-review groups! Denmark: Audit Project Odense (APO), voluntary audits and reviews, originally for Danish counties, now expanding in other European countries Source: Coenen S, et al. Lancet 21;358:1272; Thiadens HA, et al. Lancet 21;358:1272-3; Audit Project Odense, 21 report.

42 Impact of a Public Campaign for a More Rational Use of Antibiotics in Belgium, 11/2-3/21! Expect antibiotic for flu : 49% resp. (before) vs. 3% (after)! Expect antibiotic for sore throat: 32% (before) vs. 18% (after)! Less antibiotic to avoid resistance: 64% (before) vs. 75% (after)! Antibiotics must be protected: 13% (before) vs. 25% (after)! Total antibiotic sales decreased by approx. 1% Source: Beauraind I, et al. Personal communication.

43 Characteristics of Spanish vs. Danish Compendia Dimensions 3x21x7 cm 3x21x5 cm 17x11x2.5 cm Weight 3.1 kg 1.8 kg 38 g Main classif. by company by disease+alph. by disease Financing pharm. industry pharm. industry med. assoc. Guidelines no no yes (27 pages)

44 Characteristics of Primary Health Care Systems in Four EU Member States, 1997 Belgium Netherlands Denmark Sweden GP/1, inh Remuneration GPs Fee Capitation/Fee Fee Salary/Fee Rostering of patients No Yes Yes Yes Referral to specialists No Yes Yes Yes Patient pays for: - consultations - antibiotics Partially 15 25% No No No 5 1% Max./year Max./year Source: Hendrickx E, et al. 41st ICAAC, Chicago (IL), 16-19/12/21, #41.

45 Overall Consumption of Systemic Antibacterials (ATC J1) in Primary Health Care, Fee-for-Service and Rostering of Patients by GPs, EU, 1997 Consumption of antibacterials for systemic use ATC J1 (DDD per 1, inh-days) DDD/1, inh.-days NS Salary/capitation Fee-for-service Salary or Fee-forcapitation service Consumption of antibacterials for systemic use ATC J1 (DDD per 1, inh-days) DDD/1, inh.-days P <.1 Rostering No rostering Rostering No rostering of patients of patients Sources: Cars O, et al. Lancet 21; 357: , and Highlights on Health, WHO/EURO.

46 Tetracycline-R S. aureus Blood Isolates (%, 5-month moving average) STATENS SERUM INSTITUT Monthly Tetracycline Prescription Rate and Tetracycline Resistance in S. aureus Blood Isolates, Denmark, 1/ / Change in subsidization: from 5 to % (1/1996) Tetracycline Use (# prescriptions per 1, inhabitants) Source: Johansen HL, Danish Medicines Agency, and Elsberg C, Statens Serum Inst., 2.

47 Cost After Reimbursement and Consumption of Tetracyclines and Fluoroquinolones in Primary Health Care, EU Member States, Consum ption of tetracyclines for system ic use A TC J1A (DDD per 1, inh-days, 1997) [ ] [ ] A verage cost of 1 D D D of oral tetracyclin e after reim b u rsem en t (PPP US$, 1998) C onsum ption of fluoroquinolones fo r system ic use ATC J1M A (DDD per 1, inh-days,1997) [ ] [ ] A verage cost of 1 DDD of oral fluoroquinolone after re im bursem ent (P P P US$,1998) Sources: Sources: Cars O, et al. Lancet 21; 357: , and EudraMat, April 1998.

48 Ex-Factory Price and Number of Brands of Tetracyclines and Fluoroquinolones on Market, EU Member States, 1998 E x -fa c to ry p rice of 1 DDD of oral te tra c y c line (PPP US$, 1998) E x -fa c to ry price of 1 DDD of oral fluoroquinolone (P P P US$,1998) Oralte tra c y c line product nam es (N o., incl. brands and generics, 1998) Oralfluoroquinolone product nam es (N o.,incl.brands and generics,1998) Source: EudraMat, April 1998.

49 Overall Consumption of Fluoroquinolones (ATC J1MA) in Primary Health Care, Companies and Brands of Antibiotics, EU Member States, 1997 C onsum ption of te tra c yc lines fo r system ic use ATC J1A (DDD per 1, inh-days,1997) NS ( ) Oraltetracycline product nam es (N o.,incl.brands and generics,1998) Consum ption of fluoroquinolones for system ic use A TC J1M A (DDD per 1, inh-days, 1997) ( ) ( ) ( ) ( ) R 2 =.36 P= Oralfluoroquinolone product nam es (N o., incl. brands and generics) Sources: Sources: Cars O, et al. Lancet 21; 357: , and EudraMat, April 1998.

50 Overall Consumption of Systemic Antibacterials (ATC J1) in Primary Health Care, Companies and Brands of Antibiotics, EU Member States, 1997 Consum ption of antibacterials for system ic use A TC J1 (DDD per 1, inh-days) R 2 =.52 P=.8 ( ) ( ) ( ) Consum ption of antibacterials for system ic use A TC J1 (DDD per 1, inh-days) R 2 =.42 P=.1 ( ) Com panies m arketing antibiotics (N o.) Oralantibiotic product nam es (N o., incl. brands and generics) Sources: Sources: Cars O, et al. Lancet 21; 357: , and EudraMat, April 1998.

51 Pathways of Antimicrobial Use in Primary Health Care (3) Infection / Microorganism Prescription of antimicrobials Patient Over-the-counter dispensation of antimicrobials GP or specialist Pharmacist

52 Over-The-Counter (OTC) Dispensation of Antimicrobials in Europe! Anecdotal evidence from colleagues! Spain: 42% of 1, households reported having antimicrobial packages at home. Only 2/3 of these packages were the result of a physician s prescription Orero A, et al. Med Clin (Barc) 1997; 19: ! Greece: 69% and 86% of pharmacists offered antibiotics when presented with a high-fever and a low-fever rhinosinusitis scenario, respectively Contopoulos-Ioannidis DG, et al. Clin Infect Dis 21; 33: ! EC-funded project Self-medication with Antibiotics started on 1st October, 22

53 Overall Consumption of Systemic Antibacterials (ATC J1) in Primary Health Care and Consumption of Medicines Without Prescription, EU, E I FIN A UK S DK IR L C onsum ption of medicines without prescription (% interview ed,1996) R 2 =.37 P=.2 Consum ption of antibacterials for system ic use A TC J1 (DDD per 1, inh-days, 1997) Consum ption of m edicines without prescription (% int., 1996) Sources: Eurobarometer 44.3, European Commission; Cars O, et al. Lancet 21; 357:

54 Consumption of Medicines Without Prescription, No. Inhabitants per Pharmacy, and Annual Revenues from Sales of Pharmaceuticals per Pharmacy, EU, Consum ption of m edicines without prescription (% pop., 1996) , 1, 15, 2, No. inhabitants per public pharm acy (1997) Annualrevenues from sales of pharm aceuticals per public pharm acy (M illion PPP US$, 1997) R 2 =.59 P=.1 5, 1, 15, 2, No. inhabitants per public pharm acy (1997) Sources: Eurobarometer 44.3, European Commission in Key Data on Health 2, Eurostat; and GIRP and IMS Health.

55 Conclusions! Food for thought! A substantial part of the observed differences in resistance are certainly due to different levels and patterns antimicrobial use! Better understand determinants of antimicrobial use in Europe and generate hypotheses for interventions! Study the possible adverse effects of restrictive and conservative antimicrobial use!! Some missing data should soon be provided by European collaborative projects, e.g. ESAC (primary health care and hospitals), ARPAC (mainly hospitals), SAR (self-medication with antibiotics)

Initiatives taken to reduce antimicrobial resistance in DK and in the EU in the health care sector

Initiatives taken to reduce antimicrobial resistance in DK and in the EU in the health care sector Niels Frimodt-Møller Professor, MD DMSc Dept. of Clinical Microbiology Hvidovre Hospital, Copenhagen,